Pigs were challenged by injecting two classical swine fever viruses (CSFV) of the 2.1 genotype, of which two pigs exposed to CanTho3/2009 at the dose of 10 exponent 7.5 TCID50 and two pigs to DongNai4/2009 at the dose of 10 exponent 6.0 TCID50. The infected pigs showed a delayed course of sickness with typical CSFV clinical signs and viremia, and all pigs died with severe signs in 20 post-infection days. The isolate CanTho3/2009-2 from the dead pig was used to challenge three pigs that were injected cell culture CSFV vaccine. The pigs remained healthy and had no viremia although the challenge dose was 10 exponent 7.3 TCID50 of CSFV genotype 2.1, indicating CSFV genotype 2.1 did not influence the efficacy of the current CSF vaccine.